Bicyclic sulfur compounds and process for the manufacture thereof



Patented Mar. 2, 1948 i :UNITED PATENT UFF'I'CE BIGYCLIC SULFUR- COMPOUNDS "AND PROCESS FOR THE MANUFACTURE THEREOF Albert Businger, Basel, Switzerlandfirassignor to vHoflmann-La Roche Inc.,Nutley,- Ni V J a eorr-iporation of New Jersey No Drawing. Application miifil m, 19 MSerial No. 530,402. In Switzrlafid lvlay fii mli 12 Claims. (01.1260-8309) 1 z My invention relates to new bicyclic sulfur ederivatitves s 'of =1tot BilllillOFfl-thiQlpIiOBiOHiC wacid C pou ds of the formula marrying :amw'etherified -thio-groupvas well as an co (3Q eaminoi-fgroup::converted i-ntothehydantoine have Q E X ahitherto hec'ome :known; :thee-bicyehosmfuncom- L ss 3;; i 3 5 poundst according :to-omy invention:are-conse- C C H 0 quently new. H258 43311 Hzg LR According to the p 11ocesssdescribed in the presg ent speeification 'thio-ethers of 5 -mercapto- S r'nitliyl jhydantoinemust be. used asstarting ma- (A) (13) teri'a;ls.f "These' ic'ompoundsunknown iniiterature Thesubstituent .Rtmt osition. 4=ma ibe "selected 80' m y e; prep r d fr m." fi=mercapt0- from a. wide group of organic radicals, The .aminqepropionic acid or "."fromjp-mercapto-astituent R may correspond. to substituent R in -p i p 'iby fii fy the -following clatssOfstzirtingmaterials'which is mercBLptQI- -D h fi fl pfi h employed in the synthesis. The startingxmate- 151f neces ary rt n h 9im1'n0-gro1m rials are thio-ethers of S-mercaptomethyl-hyithetu'reido-group;"andth n clos nst ehydand t e of the formula tome-ring betweeni the" ureidosgroum'onthe-one hand. v a

S Q 220 The reaction scheme is irepresentedas-follows:

NHlCO Va B NH OH CHQ "The'substituent R irii Formula is"one"."which zg i or 6 H fiexertyan: activating effect upon? the adjacent C 00H SH NH? methylene group. Such's'ubs'tituents "maybeyfor example, -COOH, -CN, CO alkyl, -COSub- 5 flercapto-a-amino- ,8-Mercapto-m ureido stituted-alkyl such as -COscarboxyalkyl, pmpmic acid pmpmmc acid I V V w.Halogen epd w.Halogen cpd :=e alkylrand ill csubstituted aikyl R) a (Hal- R) -1 1 The said bicyclic sulfur compounds may bezconsidered. as -derivatives of u-aininof p-thiolproe u-3 1 2 5, 1 7 NHLG-HL'QHQ piomc ac d. The formula for this acid is repre- I S 6 S sented by. a 7

ed M as =-'N 2 fisomemmmmoon 1 1--U -Ri '1 Various suchsdenvatives have ialreadybeen pre- Ml T l mgcosure pared. Thus, for instance, the corresponding v- H' carboxymethyl-thioether is known (Journal of Y l-R ing Biologi'caltehemistry, vol. 106, yeari'i934, page QE QQQQSQ 340). The formula for this thioether is repreiNH 'R, "NH? 0 "R sented by: fil himethersof-fi-mer eapto- NH2CH CH, a e V V y "Inetliylhydantome COOH S alahaveioundzthat themewabicyclic.suliur(compounds can be obtained by treatings-with-aeon- 3 7 densingnagent, facilitating the splitting ofi of coon water; thio-ethers of 5-mercaptomethyr-hydan- Furthermorea derivative of dithiow diamino- 'fo F general formula dipropionic acid, "the amino-groups'bf -which are E transformedaintot the "ureides and subsequently Y 0'0 s into the hydantoines,: has been deseribedlitour- 0 g .nal of the American. Chemical.Society, v01. 56, ,i 2

year 1934, page 1421;The Biochemical Journal, 7

32011 27, II; yeaifi-l933apagezm38h 'ifl'oweveriz no The s'tthstituent which is notchanged during the reaction may be selected from a wide group of organic radicals. It is, however, essential that the substituent R exert an activating effect upon the adjacent methylene-group; thus, the radicals COOH, '--CN, -COX and (X standing for alkyl and substituted alkyl radicals) are particularly suitable. Practically any condensing agent facilitating the splitting off of water may be used for the purposes of the present invention, for instance concentrated sulfuric acid or phosphorus-oxychloride. The reaction sets in at room temperature more readily, however, upon warming.

It is surprising that the reaction described takes place, since it was to be expected that the oXo-group of hydantoine, as carbonyl-group of an acid-amide, would be particularly slow to react. I V

The new compounds obtained in accordance with the process described, for which the formulae have been recited at the beginning of the specification, are useful as intermediate products for the manufacture of growth-promoting substances having the action of biotine.

Example 1 The reaction of this example may be repre-' sented as follows:

Example 2 1 part by weight of 5-carboxy-pentanone(2)- thioether of 5-mercaptomethyl-hydantoine melting at I'll-172 C. (prepared from omega-bromodelta-oxo-caproic acid ester and p-mercapto-aamino-propionic acid) and 5 parts by weight of phosphorus-oxychloride are left to stand for 12 hours at room temperature. The mixture is then heated to 50 C. for one hour. Thereupon, excessive phosphorus-oxychlorlde is evaporated in vacuo. The solid, brown-yellow residue is washed with parts by weight of alcohol. Upon recrystallisation from pyridine and water in the first fraction a yellow condensation 2-substituted-3,4-ureyline-dihydrothiopene is obtained which has the summation formula C1oI-I10O3N2S and a melting point of 338-342 C., and which possesses the following formula the 2-substituent being a lactone:

4 The reaction of this example may be represented as follows:

As second fraction, there results the free 0x0 acid C10H12O4N2S in colorless crystals melting at 196-198 C. and having the following formula:

The formula for the hydantoine starting material is represented by Example 3 1 part by weight of 5-carboxy-pentanone(2)- thioether of 5-mercaptomethyl-hydantoine is heated with 5 parts by weight of concentrated sulfuric acid for 10 minutes to 50 C. On diluting with ice, a yellow powder precipitates, which is identical with the crude condensation product of Example 2.

I claim: 7 7

1. A bicyclic sulfur compound of the formula selected from the group consisting of 2. A bicyclic sulfur compound of the formula selected from the group consisting of 3. A bicyclic sulfur compound of the formula selected from the group consisting of oo(oHl)i-ooo 1 O-(CHa)aCOOH 4. Process for the manufacture of a bicyclic sulfur compound of the formula selected from the group consisting of comprising treating carboxymethyl-thioether of mercaptomethylhydantoine with a, dehydrating condensing agent.

5. Process for the manufacture of a bicyclic sulfur compound of the formula selected from the group consisting of comprising treating carboxymethyl-thioether of 5mercaptomethylhydantoine with phosphorusoxychloride.

6. Process for the manufacture of a bicyclic sulfur compound of the formula selected from the group consisting of comprising treating 5-carboxy-pentanone(2)- thioether of 5-mercaptomethylhydantoine with a dehydrating condensing agent and isolating the bicyclic sulfur compound by fractional crystallisation.

7. Process for the manufacture of a bicyclic sulfur compound of the formula selected from the group consisting of comprising treating 5-carboxy-pentanone(2)- thioether of 5-mercaptomethylhydantoine with phosphorus-oxychloride and isolating the bicyclic sulfur compound by fractional crystallisation.

6 8. Process for the manufacture of a bicyclic sulfur compound of the formula selected from the group consisting-of comprising treating 5-carboxy-pentanone(2)- thioether of 5-mercaptomethyl-hydantoine with V a dehydrating condensing agent and isolating the bicyclic sulfur compound from the mother liquor of fractional crystallisation.

9. Process for the manufacture of a bicyclic sulfur compound of the formula selected from the group consisting of comprising treating 5-carboxy-pentanone(2)- thioether of 5mercaptomethylhydantoine with concentrated sulfuric acid and isolating the bicyclic sulfur compound from the mother liquor of fractional crystallisation.

10. 2 substituted 3,4 ureyline-dihydrothiophenes the 2-substituent being a member of the group consisting of COOH, CN, CO alkyl, CO carboxyalkyl and the lactone thereof.

11. Process for the manufacture of Z-substituted-3,4-urey1ine-dihydrothiophenes, the 2-substituent being a member of the group consisting of COOH, CN, CO alkyl, CO carboxyalkyl and the lactone thereof, which comprises treating an activated methylene thio-ether of 5- mercaptomethyl-hydantoine with a dehydrating condensing agent.

12. Process for the manufacture of 2-substituted-3A-urey1ine-dihydrothiophenes, the 2-substituent being a member of the group consisting of COOH, -CN, CO alkyl, CO carboxyalkyl and the lactone thereof, which comprises treating an activated methylene thio-ether of 5- mercaptomethyl-hydantoine with phosphorusoxychloride.

ALBERT BUSINGER.

REFERENCES CITED The following references are of record in the file of this patent:

Science, November 20, 1942, pages 455-461. 

